Benzotriazines



Patented Nov. 29, 1949 Y BENZOTRIAZINES Frank J. Wolf, Westfield, and Karl Pfistcr, III, Elizabeth, N. J assignors to Merck & 00., Inc., Rahway, N. J., a corporation of New Jersey No Drawing. Application January 10, 1947, Serial No. 721,476

Claims.

This invention relates to new organic chemical compounds having therapeutic activity, and to methods by which they may be prepared from readily available starting materials. More particularly the invention relates to the preparation of 7-halogen-3-(monoand di-substituted amino) -benzotriazine-1,2,4 compounds, and to the chemical compounds so produced which are useful intermediates in the preparation of complex organic compounds including antimalarial agents and dyes.

The new compounds of the present invention are prepared from 7-halogen-3-chloro-benzotri-' wine-1,2,4 compounds by reacting with a monoor (ll-substituted amine preferably by heating in an organic solvent such as carbon tetrachloride, and the like. The starting 3-chloro compounds can be prepared by reacting a 4-halogen-2-nitroaniline with phosgene in organic solvent solution, treating the reaction mixture thus obtained with anhydrous ammonia to form the corre-' sponding 4-halogen-2-nitrophenyl urea, reacting this product with sodium hydroxide and then acidifying to precipitate the 7-halogen-3-hydoxy-benzotriazine-1,2,4-oxide-1, as fully disclosed in our companion application, Serial No. 721,470 filed January 10, 1947. The oxide is then reduced to the 7-halogen-3-hydroxy-benzotriazine-1,2,4 in the manner disclosed in our companion application Serial No. 721,474 filed January 10, 1947; and the same reacted with phosphorous oxychloride and a dialkyl aniline as disclosed in our companion application Serial No. 721,475 filed January 10, 1947, to form the 7-halogen-3-chloro-benzotriazine-1,2,4.

The reaction in forming the 3-(monoand disubstituted amino) compounds can be represented as follows:

wherein R1 is a hydrogen, alkyl, aryl, or aralkyl group; R2 is an alkyl, aryl, or aralkyl group, and wherein R1 and R2 together form part of an N- or O-heterocyclic radical.

An alternate procedure for preparing the substituted amino compounds is by reduction of the oxide-1 form of the corresponding 3-(monoor di-substituted amino) compound prepared as disclosed in our companion application Serial No. 721,472 filed January 10, 1947. The reduction is preferably carried out by reacting the oxide-1 compound with phosphorous and iodine 2 preferably by heating to reflux in a suitable solvent such as glacial acetic acid. This reaction can be represented as follows:

wherein R1 is a hydrogen, alkyl, aryl, or aralkyl radical; R2 is an alkyl, aryl, or aralkyl radical; and R1 and R2 together can form part of an N- or O-heterocyclic radical.

A third procedure possible for the preparation of 3-(mono-benzyl-amino) substituted compounds comprises reacting a 7-halogen-3-aminobenzotriazine-1,2,4 compound, prepared as described in our pending application Serial No. 661,083 filed April 10, 1946; or the corresponding oxide-1 compound prepared as described in our pending application Serial No. 661,084 filed April 10, 1946, with benzylamine, preferably by heating to reflux a mixture of the reactants. The same product, i. e. 7-halogen-3-(mono-benzylamino) -benzotriazine-1,2,4, is obtained from both starting materials, and is recovered as a precipitate which can readily be purified by recrystallization from Cellosolve.

The following examples show how procedures of the present invention can be carried out, but it is to be understood that these examples are given by Way of illustration and not of limitation.

Example 1 A mixture of 9.7 gm. of 7-bromo-3-aminobenzotriazine-1,2,4-oxide-1 and ml. of benzylamine were refluxed for 8 hours. The solution was cooled and poured into 500 ml. of methanol. The resulting precipitate was filtered and washed with ml. of methanol. The crude product was recrystallized from Cellosolve. A yield of 5.0 gms. of 7-bromo-3-benzylamino benzotriazine 1,2,4, M. P. 172-3", 40% of the theoretical amount was obtained.

Example 2 A mixture of 3.5 gms. of 7-chloro-3-aminobenzotriazine-1,2,4 and 15 ml. of benzylamine was heated at reflux for three-quarters of an hour. The solution was cooled and the resulting precipitate triturated with 25 ml. of ether and filtered. The yellow material was crystallized from Cellosolve and 4.2 gms. of 7-chloro-3-benzylamino-benzotriazine-1,2,4 was obtained, M. P. 175 C., 78% of the theoretical amount.

Example 3 Example 4 Two grams of red phosphorus. and 1.0. gm, of.- iodine were dissolved in 50 m l. of, glacial acetic acid. Then 5.0 gms. of 7-Ch10lI-Qr3ndiFHrD10PYlr amino-benzotriazine 1,2,4 oxide-1 were added with 2 cc. of water and the solution refiuxedfor. 1 /2 hours. The solution Was filtered while hot and the acetic acid solution was concentrated to;

a small volume. The residue was recrystallized from an, alcoholrwater mixture.

amine-1,2,4 71% M. P. 66?.

Example 5 By the process as described in Example 4 starting with, 7-chloro-3 -butylamino-benzotriaZine-. 1,2,4-oxide-1, the. compound 7-chloro-3-n-butylamino-benzotriazine-1,2,4, M. P. 150-1" 0., is obtained in a 69% yield.

Example 6;

By the process as described' in, Example 4 '7- chl'oro-3-[(4'-pentyl 1 die-thylamino)-amino]'- benzotriazine-l,2,4-oXide-1 is converted to, 7- chloro-3[ (4'-pent-yl=- 1- diethylamino) amino]- benzotriazine-1,2;4, B, P. 70C; at 3'microns..

Example-7 By theprocess' as described in Example 4 7'- chlor0-3-.N methylanilinobenzotriazine 1,2,4- oxide-l is converted to 7-chloro-3-N-methylanilino-benzotriazine-1,2;4 M. P; 145-6 0., in 52%.yield'.

Obtained 3.3; grna. of. 7-chloro-3=di-n-prop1yamino-benzotri,

It will also be understood that many other '7- halogen-3(monoand di-substituted amino)- benzotriazine-l,2,4-oXide-1 compounds, including all of such compounds disclosed in our copending application Serial No. 721,472, filed January 10, 1947, can be converted to the corresponding 7s-halogen-3imonoand di-substituted-aminM- benzotriazine-1 ,2;4- compounds by theprocess as described in Example 4.

Modifications can be made in the foregoing procedures. without departing from the spirit and scope of the present invention and We are to be limited only by theappended claims.

Weclaim:

1 7-halogen-benzotriazine-1,2,4 having in the 3.-p.o,sition.a substituent selected from the class consisting of benzylamino (4-pentyl-l-diethylamino) -amino, N-methylanilino, n-butylamino, and= di-n-propylamino radicals.

2. 7-ha1ogen 3 benzylamino-benzotriazine- 1.2.4:.

3. T-chloro, 3 benzylamino-benzotriazina.

4., 7-chloro-3- (41- nentyll-diethylamino) amianoil. -benzo t-riazine- 1 ,2;4-..

5;. 7-01110110?BrN-HlGthYlfiHiliHQ benzotriazine FRANK, J. WQLF. KARL :E'FISTER',v III.

REFERENCES CITED The following references are of record in the me ofthis patent:

UNITED STATES.- PATENTSv Arndt; Berichte-150. (19137), pp; 1248-1261. l?.arkes,.J. Chem..Soc; (:1938'), pp. 1842-1843. 

